1. Field of the Invention
This invention relates to a pH sensitive gum composition capable of delivering a pharmaceutical agent in convenient liquid or gel form to its point of application. More particularly, this invention relates to a pharmaceutical delivery system and a method for the controlled administration of drug to a patient. This invention also relates to a pharmaceutical delivery system possessing the property of being liquid at a pH of less than about 3.5-5 and a gel at a pH of greater than about 5. In preferred embodiments, the invention relates to bioerodable drug delivery systems for the controlled administration of drug to a mammalian patient over a prolonged period of time, especially to the eye of such patient. In another aspect the invention relates to the reversibility of the system from liquid to gel and gel to liquid thereby enabling varied methods of application suited to the different biological environments encountered in a mammalian patient. Another aspect of the invention relates to a method for preparing these compositions. A further aspect of this invention relates to the use of these compositions as adjuvants in pharmaceutical formulations to potentiate the response of therapeutic agents.
2. Description of the Prior Art
The prior art is replete with a multiplicity of compositions, products, appliances, applications, dispensers, injectors, depositors for the controlled administration of drug to a mammalian patient. Typically, such products provide a means to carefully regulate the level of drug administration to the patient and also maintain a more uniform and therapeutically effective blood level, thus increasing the effectiveness of the desired treatment.
These products have been in the form of liquids, ointments, tablets, capsules, inserts all and other vehicles having bioerodable properties and/or non-bioerodable properties. Each of these products, depending on its use or application, possess inherent advantages and disadvantages. For example, liquid compositions for dropwise instillation to the eye provide ease of formulation; but accurate administration of the required amount of drug is difficult, as illustrated by the drops of the ophthalmic streaming down the face of the patient during its administration.
Exemplary of insert type drug products are U.S. Pat. Nos. 3,618,604 and 3,867,519. The former illustrates the non-bioerodable type of ocular insert for controlled drug administration while the latter teaches the use of a bioerodable ocular insert. These inventions, however, require relatively detailed and complex preparatory techniques. Furthermore, with both types of inserts, the patients may suffer irritation, discomfort, dislocation and/or bacterial contamination via their placement or migration within the eye.
Other disadvantages associated with the non-bioerodable drug product, device, or vehicle are more apparent when such devices are employed in areas of the anatomy other than the eye, and surgical or other professional removal is necessary.
Tablets and the like, whether or not bioerodable, suffer the inherent disadvantages of solid preparation techniques.
In other aspects of drug products vehicles and compositions, the prior art teaches the use of various gums and polymers to potentiate the pharmacological response of drugs. In this connection, for example, the use of methyl cellulose, hydroxymethyl cellulose, guar gum, polyvinyl alcohol, diethylaminoethyl dextran, alginic acid and others is familiar to those skilled in the art. Some of these gums, polymers, and others are also used in eye preparations.
U.S. Pat. Nos. 3,557,016 and 3,519,434, disclose the making of a heat reversible aqueous gel composition, containing xanthan and locust bean gums, and its application to various food preparations. These disclosures, however, do not teach that reversible gel compositions of these gums, sensitive to factors other than heat, can be prepared nor how to use such compositions in drug delivery or as a vehicle. U.S. Pat. Nos. 3,700,451 and 3,944,427 disclose gelable and gelled compositions containing a liquid medium, agar and a combination of xanthan and locust bean gums. These compositions are said to be useful to process photosensitive media and as a carrier for therapeutic agents. These compositions, however, will not produce reversible liquid-gel properties dependent on pH variability, but are gels at all disclosed concentrations.